ABSTRACT Prevention of influenza is particularly important for patients with end-stage renal disease (ESRD) due to increased risk for severe complications from influenza or influenza-related hospitalizations, mortality, and healthcare costs. To reduce the burden of influenza in patients with ESRD, the Advisory Committee on Immunization Practices (ACIP) has long recommended influenza immunization. Yet, immunogenicity evidence demonstrates that patients on dialysis have lower immune responses to standard influenza vaccine and effectiveness studies suggest that the standard vaccine does not prevent influenza-related outcomes. Alternate vaccines and vaccination strategies are available, including the high-dose influenza vaccine or repeat doses administered during the same influenza season. Trivalent, high-dose inactivated, influenza vaccine was licensed by the United States Food & Drug Administration in December 2009 for adults, aged 65 years and older, to induce higher antibody responses resulting in better protection from influenza than the standard vaccine. The effectiveness and safety of alternate influenza prevention strategies have yet to be investigated in the dialysis population. Evaluating the benefits and risks of influenza immunization in dialysis patients is challenging because clinical trials frequently exclude immunocompromised patients. Also, nonexperimental studies of vaccines can be subject to strong bias because healthier patients are more likely to receive immunization. We propose to conduct an effectiveness and safety study using existing data from the United States Renal Data System ? a data source containing detailed medical data on a large population of patients with ESRD. The large size of our study will allow us to characterize small differences in vaccine effectiveness and safety between influenza immunization with a) high-dose vs. standard-dose vaccines; and b) a repeat standard dose vs. a single standard dose during the same influenza season. Our vaccine effectiveness analyses will incorporate a broad range of influenza-related outcomes. Our safety analyses will focus on a priori identified adverse events after influenza immunization that have been previously suggested as well as use novel data-driven signal detection methods to identify previously unreported adverse reactions specific to the dialysis population. Results from this research will provide important evidence for clinical decisions about the risks and benefits of alternate influenza immunization strategies in the dialysis population. This study will also contribute to the development of statistical methodologies that can be used for research on vaccine effectiveness and safety.